U.S. patent application number 17/056506 was filed with the patent office on 2021-07-08 for noninvasive cranial nerve therapy.
The applicant listed for this patent is MUSC Foundation for Research Development. Invention is credited to Bashar Badran, Daniel Cook, Mark George, Doe Jenkins.
Application Number | 20210205606 17/056506 |
Document ID | / |
Family ID | 1000005465413 |
Filed Date | 2021-07-08 |
United States Patent
Application |
20210205606 |
Kind Code |
A1 |
Badran; Bashar ; et
al. |
July 8, 2021 |
NONINVASIVE CRANIAL NERVE THERAPY
Abstract
The present invention relates to systems for providing
noninvasive cranial nerve stimulation and methods for using the
same. The present invention administers therapy through electrodes
that are noninvasively attached to one or more of a subject's
cranial nerve. The systems can be used to enhancing rehabilitation
and recovery by improving neuroplasticity and coupling muscle
training with feedback.
Inventors: |
Badran; Bashar; (San Ramon,
CA) ; George; Mark; (Sullivans Island, SC) ;
Jenkins; Doe; (Johns Island, SC) ; Cook; Daniel;
(Charleston, SC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MUSC Foundation for Research Development |
Charleston |
SC |
US |
|
|
Family ID: |
1000005465413 |
Appl. No.: |
17/056506 |
Filed: |
May 20, 2019 |
PCT Filed: |
May 20, 2019 |
PCT NO: |
PCT/US2019/033151 |
371 Date: |
November 18, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62673578 |
May 18, 2018 |
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62757775 |
Nov 9, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 1/36036 20170801;
A61N 1/0456 20130101; A61N 1/0452 20130101; A61N 1/36031 20170801;
A61N 1/36034 20170801 |
International
Class: |
A61N 1/04 20060101
A61N001/04; A61N 1/36 20060101 A61N001/36 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] This invention was made with government support under Grant
No. P2HCD086844 awarded by the National Institute of Health. The
government has certain rights in the invention.
Claims
1-20. (canceled)
21. A method of enhancing oromotor skills, comprising the steps of:
providing a cranial nerve stimulation system comprising at least
one stimulating electrode; securing the at least one stimulating
electrode to a subject's cranial nerve; providing the subject with
a source of food; and administering stimulation using the at least
one stimulating electrode to the cranial nerve.
22. The method of claim 21, wherein the step of administering
stimulation is triggered by at least one physiological response
from the subject.
23. The method of claim 22, wherein the at least one physiological
response is a feeding attempt by the subject.
24. The method of claim 22, wherein the at least one physiological
response is a visual sucking attempt by the subject.
25. The method of claim 22, wherein the at least one physiological
response is a muscle activation by the subject that surpasses a
minimum threshold value.
26. The method of claim 21, wherein the cranial nerve is selected
from the group consisting of: the trigeminal nerve, the facial
nerve, the accessory nerve, the hypoglossal nerve, the auricular
branch of the vagus nerve, and the main bundle of the vagus
nerve.
27. The method of claim 21, wherein the at least one stimulating
electrode is noninvasively secured to a subject's ear canal,
tragus, cymba conchae, lobe, helix, anti-helix, mastoid, or
neck.
28. The method of claim 25, wherein the minimum threshold is an
absolute value selected from the group consisting of about: 0.1
.mu.V, 0.5 .mu.V, 1 .mu.V, 5 .mu.V, 10 .mu.V, 50 .mu.V, 100 .mu.V,
200 .mu.V, 300 .mu.V, 400 .mu.V, 500 .mu.V, 1 mV, 5 mV 10 mV, 20
mV, 30 mV 40 mV, or 50 mV.
29. The method of claim 25, wherein the minimum threshold is a
change from a base measurement taken at rest selected from the
group consisting of about: 0.1 .mu.V, 0.5 .mu.V, 1 .mu.V, 5 .mu.V,
10 .mu.V, 50 .mu.V, 100 .mu.V, 200 .mu.V, 300 .mu.V, 400 .mu.V, 500
.mu.V, 1 mV, 5 mV, 10 mV, 20 mV, 30 mV, 40 mV, or 50 mV.
30. The method of claim 25, wherein the minimum threshold is a
percentage of a maximum potential of the muscle selected from the
group consisting of about: 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%,
30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or
95%.
31. The method of claim 21, wherein the stimulation has an
intensity selected from the group consisting of about: 0.01 mA,
0.05 mA, 0.1 mA, 0.2 mA, 0.3 mA, 0.4 mA, 0.5 mA, 0.6 mA, 0.7 mA,
0.8 mA, 0.9 mA, 1 mA, 1.5 mA, 2 mA, 2.5 mA, 3 mA, 3.5 mA, 4 mA, 4.5
mA, 5 mA, 6 mA, 7 mA, 8 mA, 9 mA, and 10 mA.
32. The method of claim 21, wherein the stimulation has a frequency
selected from the group consisting of about: 1 Hz, 2 Hz, 3 Hz, 4
Hz, 5 Hz, 6 Hz, 7 Hz, 8 Hz, 9 Hz, 10 Hz 15 Hz, 20 Hz, 25 Hz, 30 Hz,
35 Hz, 40 Hz, 45 Hz, and 50 Hz.
33. The method of claim 21 wherein the stimulation has a pulse
width selected from the group consisting of about: 10 .mu.s, 20
.mu.s, 30 .mu.s, 40 .mu.s, 50 .mu.s, 60 .mu.s, 70 .mu.s, 80 .mu.s,
90 .mu.s, 100 .mu.s, 150 .mu.s, 200 .mu.s, 250 .mu.s, 300 .mu.s,
350 .mu.s, 400 .mu.s, 450 .mu.s, 500 .mu.s, 550 .mu.s, 600 .mu.s,
650 .mu.s, 700 .mu.s, 750 .mu.s, 800 .mu.s, 850 .mu.s, 900 .mu.s,
950 .mu.s, and 1 ms.
34. The method of claim 21, wherein the stimulation has an on
duration and an off duration, each selected from the group
consisting of about: 0.1 seconds, 0.5 seconds, 1.5 seconds. 2
seconds, 2.5 seconds, 3 seconds, 3.5 seconds, 4 seconds, 4.5
seconds, 5 seconds, 10 seconds, 20 seconds, 30 seconds, 40 seconds,
50 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes,
10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 45
minutes, 50 minutes, and 1 hour.
35. A method of enhancing muscle rehabilitation, comprising the
steps of providing a cranial nerve stimulation system comprising at
least one stimulating electrode; securing the at least one
stimulating electrode to a subject's cranial nerve; measuring
muscle group activation; and administering stimulation using the at
least one stimulating electrode to the cranial nerve in response to
the measurement of muscle group activation when the measurement
surpasses a minimum threshold value.
36. The method of claim 35, wherein the cranial nerve is selected
from the group consisting of: the trigeminal nerve, the facial
nerve, the accessory nerve, the hypoglossal nerve, the auricular
branch of the vagus nerve, and the main bundle of the vagus
nerve.
37. The method of claim 35. wherein the minimum threshold is an
absolute value selected from the group consisting of about: 0.1
.mu.V, 0.5 .mu.V, 1 .mu.V, 5 .mu.V, 10 .mu.V, 50 .mu.V, 100 .mu.V,
200 .mu.V, 300 .mu.V, 400 .mu.V, 500 .mu.V, 1 mV, 5 mV, 10 mV, 20
mV, 30 mV, 40 mV, or 50 mV.
38. The method of claim 35, wherein the minimum threshold is a
change from a base measurement taken at rest selected from the
group consisting of about: 0.1 .mu.V, 0.5 .mu.V, 1 .mu.V, 5 .mu.V,
10 .mu.V, 50 .mu.V, 100 .mu.V, 200 .mu.V, 300 .mu.V, 400 .mu.V, 500
.mu.V, 1 mV, 5 mV, 10 mV, 20 mV, 30 mV, 40 mV, or 50 mV.
39. The method of claim 35, wherein the minimum threshold is a
percentage of a maximum potential of the muscle selected from the
group consisting of about: 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%,
30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or
95%.
40. A system for enhancing oromotor skills of a subject,
comprising: a power source; at least one stimulating electrode
configured for positioning on a subject's cranial nerve; and a
computing platform including a processor and a non-transitory
computer-readable medium communicatively connected to the at least
one stimulating electrode; wherein the computing platform is
configured to instruct the at least one stimulating electrode to
deliver a stimulation when a physiological response is detected
from the subject.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application No. 62/673,578, filed May 18, 2018, and to U.S.
Provisional Patent Application No. 62/757,775, filed Nov. 9, 2018,
the contents of which are each incorporated by reference herein in
their entirety.
BACKGROUND OF THE INVENTION
[0003] Preterm infants and term infants who suffer hypoxic ischemic
encephalopathy (HIE) are at high risk for motor problems, which
primarily manifest as feeding delays during their neonatal hospital
admission. Oromotor dyscoordination is very common in both groups
of infants, and typically takes 3-6 weeks of working on oral
feedings in the hospital before the infant may take enough breast
milk or formula to sustain adequate growth for discharge.
Occupational therapy usually works with infants once a day to
ensure that the feeding particulars, such as nipple choice,
frequency of oral feeding, do not tax infant physiology too greatly
and to guide learning this motor skill. Feeding difficulty is the
primary reason for delayed discharge of preterm or HIE infants.
Many of these infants will not be able to master this motor skill
before term age (40-42 weeks gestation) and will receive a
gastrostomy tube (G-tube) for direct gastric feeding, in order that
they may finally be discharged from the hospital to home. Neonatal
intensive care units (NICU) place on average 40 G-tubes per year.
This procedure requires general anesthesia for both insertion and
eventual take down, and leaves scars in the epigastric area. The
g-tube also reinforces the parental perception that their child is
not normal and that he or she has a more limited developmental
potential than a `normal` child.
[0004] Even with significant brain injury, it is known that
neuroplasticity in infants may lead to improved, and even near
normal outcomes. This neuroplasticity involves stimulating
neurogenesis and reparative inter-neuronal connections to improve
motor skills in neonatal animal models and in adults after stroke.
In addition, it is known that rehabilitative training may be
enhanced by brain stimulation using a variety of modalities.
[0005] Feeding in neonates involves a sequence of sucking,
swallowing, and breathing that requires coordination of the face,
head, and neck muscles with the myelinated vagal regulation of the
bronchi and the heart. In preterm neonates, the muscles needed to
feed are underdeveloped, resulting in the need for OT
rehabilitation to `learn` feeding patterns. Preterm neonates'
inability to feed effectively is the primary reason for prolonged
hospital stays. In neonates with HIE, development of cortex and
basal ganglia is interrupted, and depending on the severity, normal
developmental plasticity is hindered, further contributing to their
inability to feed. Both types of feeding difficulties involve
complex motor learning, which requires integration of sensory and
motor pathways.
[0006] Thus, there is a need in the art for improved systems and
methods for administering neural stimulation for enhancing
neuroplasticity and muscle training. The present invention meets
this need.
SUMMARY OF THE INVENTION
[0007] In one aspect, the present invention provides a method of
enhancing oromotor skills, comprising the steps of: providing a
cranial nerve stimulation system comprising at least one sensing
electrode and at least one stimulating electrode; securing the at
least one sensing electrode adjacent to a subject's cheek or jaw
muscle and the at least one stimulating electrode to a subject's
cranial nerve; providing the subject with a source of food;
measuring muscle activation using the at least one sensing
electrode that surpasses a minimum threshold; and administering
stimulation using the at least one stimulating electrode to the
cranial nerve in response to the measurement of muscle activation
surpassing the minimum threshold.
[0008] In one embodiment, the cranial nerve is selected from the
group consisting of: the trigeminal nerve, the facial nerve, the
accessory nerve, the hypoglossal nerve, the auricular branch of the
vagus nerve, and the main bundle of the vagus nerve. In one
embodiment, the measuring step and the administering step are
repeated in a closed loop. In one embodiment, the at least one
stimulating electrode is noninvasively secured to a subject's ear
canal, tragus, cymba conchae, lobe, helix, anti-helix, mastoid, or
neck. In one embodiment, the minimum threshold is an absolute value
selected from the group consisting of about: 0.1 .mu.V, 0.5 .mu.V,
1 .mu.V, 5 .mu.V, 10 .mu.V, 50 .mu.V, 100 .mu.V, 200 .mu.V, 300
.mu.V, 400 .mu.V, 500 .mu.V, 1 mV, 5 mV, 10 mV, 20 mV, 30 mV, 40
mV, or 50 mV. In one embodiment, the minimum threshold is a change
from a base measurement taken at rest selected from the group
consisting of about: 0.1 .mu.V, 0.5 .mu.V, 1 .mu.V, 5 .mu.V, 10
.mu.V, 50 .mu.V, 100 .mu.V, 200 .mu.V, 300 .mu.V, 400 .mu.V, 500
.mu.V, 1 mV, 5 mV, 10 mV, 20 mV, 30 mV, 40 mV, or 50 mV. In one
embodiment, the minimum threshold is a percentage of a maximum
potential of the muscle selected from the group consisting of
about: 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,
50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. In one
embodiment, the stimulation has an intensity selected from the
group consisting of about: 0.01 mA, 0.05 mA, 0.1 mA, 0.2 mA, 0.3
mA, 0.4 mA, 0.5 mA, 0.6 mA, 0.7 mA, 0.8 mA, 0.9 mA, 1 mA, 1.5 mA, 2
mA, 2.5 mA, 3 mA, 3.5 mA, 4 mA. 4.5 mA, 5 mA. 6 mA, 7 mA, 8 mA, 9
mA, and 10 mA. In one embodiment, the stimulation has a frequency
selected from the group consisting of about: 1 Hz, 2 Hz, 3 Hz, 4
Hz, 5 Hz, 6 Hz, 7 Hz, 8 Hz, 9 Hz, 10 Hz, 15 Hz, 20 Hz, 25 Hz, 30
Hz, 35 Hz, 40
[0009] Hz, 45 Hz, and 50 Hz. In one embodiment, the stimulation has
a pulse width selected from the group consisting of about: 10
.mu.s, 20 .mu.s, 30 .mu.s, 40 .mu.s, 50 .mu.s, 60 .mu.s, 70 .mu.s,
80 .mu.s, 90 .mu.s, 100 .mu.s, 150 .mu.s, 200 .mu.s, 250 .mu.s, 300
.mu.s, 350 .mu.s, 400 .mu.s, 450 .mu.s, 500 .mu.s, 550 .mu.s, 600
.mu.s, 650 .mu.s, 700 .mu.s, 750 .mu.s, 800 .mu.s, 850 .mu.s, 900
.mu.s, 950 .mu.s, and 1 ms. In one embodiment, the stimulation has
an on duration and an off duration, each selected from the group
consisting of about: 0.1 seconds, 0.5 seconds, 1.5 seconds, 2
seconds, 2.5 seconds, 3 seconds, 3.5 seconds, 4 seconds, 4.5
seconds, 5 seconds, 10 seconds, 20 seconds, 30 seconds, 40 seconds,
50 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes,
10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 45
minutes, 50 minutes, and 1 hour.
[0010] In another aspect, the present invention provides a cranial
nerve stimulation system, comprising: at least one sensing
electrode configured to attach adjacent to at least one muscle; and
at least one stimulating electrode configured to attach adjacent to
a cranial nerve; wherein the at least one stimulating electrode is
electrically linked to the at least one sensing electrode such that
the at least one stimulating electrode is activated to stimulate
the cranial nerve when the at least one sensing electrode measures
electrical energy in the at least one muscle that passes a minimum
threshold.
[0011] In one embodiment, the at least one cranial nerve is
selected from the group consisting of: the trigeminal nerve, the
facial nerve, the accessory nerve, the hypoglossal nerve, the
auricular branch of the vagus nerve, and the main bundle of the
vagus nerve.
[0012] In one embodiment, the system further comprises a power
source, a transmitter, and a processor communicatively connected to
a non-transitory computer-readable memory with instructions store
thereon, which when executed by the processor, initiates a
closed-loop synchronization between activation and deactivation of
the at least one stimulating electrode with the at least one
sensing electrode measuring electrical energy that passes a minimum
threshold.
[0013] In one embodiment, the system further comprises a feeding
bottle comprising at least one sensor, a power source, and a
transmitter. In one embodiment, the at least one sensor is selected
from the group consisting of: a flow sensor, a pressure sensor, a
suction sensor, a gyroscope, an accelerometer, a temperature
sensor, and a volume sensor. In one embodiment, the system further
comprises a power source, a transmitter, and a processor
communicatively connected to a non-transitory computer-readable
memory with instructions store thereon, which when executed by the
processor, synchronize activation and deactivation of the at least
one stimulating electrode with the at least one sensor sensing
feeding from the bottle and cessation of feeding from the
bottle.
[0014] In another aspect, the present invention provides a method
of enhancing muscle rehabilitation, comprising the steps of:
providing a cranial nerve stimulation system comprising at least
one sensing electrode and at least one stimulating electrode;
[0015] securing the at least one sensing electrode adjacent to a
subject's muscle group of interest and the at least one stimulating
electrode to a subject's cranial nerve; measuring muscle group
activation using the at least one sensing electrode that surpasses
a minimum threshold; and administering stimulation using the at
least one stimulating electrode to the cranial nerve in response to
the measurement of muscle group activation surpassing the minimum
threshold.
[0016] In one embodiment, the cranial nerve is selected from the
group consisting of: the trigeminal nerve, the facial nerve, the
accessory nerve, the hypoglossal nerve, the auricular branch of the
vagus nerve, and the main bundle of the vagus nerve. In one
embodiment, the measuring step and the administering step are
repeated in a closed loop.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] The following detailed description of exemplary embodiments
of the invention will be better understood when read in conjunction
with the appended drawings. It should be understood, however, that
the invention is not limited to the precise arrangements and
instrumentalities of the embodiments shown in the drawings.
[0018] FIG. 1A and FIG. 1B depict diagrams showing exemplary
systems for pairing noninvasive cranial nerve stimulation with
neonate feeding.
[0019] FIG. 2 depicts a diagram showing an exemplary system for
triggering cranial nerve stimulation in neonate feeding.
[0020] FIG. 3 depicts a diagram showing an exemplary system for
triggering cranial nerve stimulation in muscle rehabilitation.
[0021] FIG. 4 depicts a flowchart for an exemplary method of
training neonate feeding.
[0022] FIG. 5 depicts a flowchart for an exemplary method of
training muscle rehabilitation.
[0023] FIG. 6 depicts exemplary electromyography electrode
placement for muscle activation detection and stimulation in
training neonate feeding behavior.
[0024] FIG. 7 depicts the results of experiments investigating
optimal electrode placement that delivers the most reliable
stimulation trigger induced by a visual suck in neonate
feeding.
[0025] FIG. 8 depicts the results of experiments investigating
optimal electrode placement that delivers the highest rate of
stimulation when a visual suck is recorded in neonate feeding.
[0026] FIG. 9 depicts historical feeding data in a sample of
infants having feeding difficulty.
[0027] FIG. 10 depicts the results of administering cranial nerve
therapy to 14 babies having feeding difficulty.
[0028] FIG. 11 depicts the results of statistical analysis for the
8 responders in the treatment group shown in FIG. 10; the
responders have significant changes in their oral feeding behavior,
indicated by significant changes in the slopes of their linear
regression lines.
[0029] FIG. 12 depicts the results of statistical analysis for the
6 non-responders in the treatment group shown in FIG. 10; the
non-responders have linear regression slopes that are
non-significantly different from zero, indicating that no
improvement has been achieved.
[0030] FIG. 13A and FIG. 13B depict the results of experiments
investigating the effect of cranial nerve therapy on brain white
matter tract integrity in infants. FIG. 13A shows fractional
anisotropy (FA) change per week between responders (full feed) and
non-responders (G-tube) in the Left External Capsule and Right
Corpus Callosum, two white matter regions of interest important in
motor integration. FIG. 13B shows axial kurtosis (K.sub..parallel.)
change per week between responders (full feed) and non-responders
(G-tube) in Left Posterior Thalamic Radiations (PTR) and Right
Inferior Front-Occipital Fasciculus (IFOF), two white matter
regions of interest important in sensorimotor integration.
DETAILED DESCRIPTION
[0031] It is to be understood that the figures and descriptions of
the present invention have been simplified to illustrate elements
that are relevant for a clear understanding of the present
invention, while eliminating, for the purpose of clarity, many
other elements typically found in the art. Those of ordinary skill
in the art may recognize that other elements and/or steps are
desirable and/or required in implementing the present invention.
However, because such elements and steps are well known in the art,
and because they do not facilitate a better understanding of the
present invention, a discussion of such elements and steps is not
provided herein. The disclosure herein is directed to all such
variations and modifications to such elements and methods known to
those skilled in the art.
[0032] Unless defined elsewhere, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, exemplary methods and materials are described.
[0033] As used herein, each of the following terms has the meaning
associated with it in this section.
[0034] The articles "a" and "an" are used herein to refer to one or
to more than one (i.e., to at least one) of the grammatical object
of the article. By way of example, "an element" means one element
or more than one element.
[0035] "About" as used herein when referring to a measurable value
such as an amount, a temporal duration, and the like, is meant to
encompass variations of .+-.20%, .+-.10%, .+-.5%, .+-.1%, and
.+-.0.1% from the specified value, as such variations are
appropriate.
[0036] Throughout this disclosure, various aspects of the invention
can be presented in a range format. It should be understood that
the description in range format is merely for convenience and
brevity and should not be construed as an inflexible limitation on
the scope of the invention. Accordingly, the description of a range
should be considered to have specifically disclosed all the
possible subranges as well as individual numerical values within
that range. For example, description of a range such as from 1 to 6
should be considered to have specifically disclosed subranges such
as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6,
from 3 to 6, etc., as well as individual numbers within that range,
for example, 1, 2, 2.7, 3, 4, 5, 5.3, 6, and any whole and partial
increments there between. This applies regardless of the breadth of
the range.
Cranial Nerve Stimulation Systems
[0037] The present invention is based in part on systems for
providing noninvasive cranial nerve stimulation. The systems
administer therapy through electrodes that are noninvasively
attached to one or more of a subject's cranial nerve. The systems
can be used to enhancing rehabilitation and recovery by improving
neuroplasticity and coupling muscle training with feedback.
[0038] Stimulation can be noninvasively administered to any
suitable cranial nerve. Non-limiting examples include the
trigeminal nerve, the facial nerve, the accessory nerve, the
hypoglossal nerve, the auricular branch of the vagus nerve, the
main bundle of the vagus nerve, and the like. The auricular branch
of the vagus nerve can be accessed in a variety of ways, including
but not limited to the ear canal, the tragus, the cymba conchae,
the outer ear, the mastoid, and combinations thereof. The main
bundle of the vagus nerve can be accessed at any suitable location
along the neck. In various embodiments, the stimulation is
administered transcutaneously. Stimulation can be administered
using one or more electrodes secured adjacent to a cranial nerve in
any suitable manner, including but not limited to using an
adhesive, a clip, a patch, an ear plug, a head band, a neck brace,
a collar, a head covering, and the like.
[0039] In some embodiments, the present invention provides
therapeutic tools aimed at improving and accelerating learned
feeding behavior in neonates. The systems provided change the way
rehabilitation is conducted for preterm neonates, resulting in
earlier discharge, lower hospital costs, improved parental
perception of the developmental potential of their infant, and
reduces stress and improves bonding with parents, both in and out
of the hospital. The systems can serve as a take-home feeding aid
for convalescing critically ill infants who have missed the
developmental window to master the feeding skill, and for infants
with congenital syndromes that make oral feeding challenging.
[0040] Treating oromotor difficulties during the learned task of
feeding with noninvasive brain stimulation that promotes
plasticity, poses a highly novel application of transcutaneous
auricular vagus nerve stimulation (taVNS). The major premise is
that in babies at high risk for motor problems, simultaneously
delivered brain stimulation via taVNS will boost motor cortical
plasticity involved in a learned feeding task, leading to better
feeding. There may be a synergistic effect of surgically implanted
VNS when combined with a paired stimulus that directs plastic
changes to occur in the cortex. This invention utilizes novel forms
of noninvasive vagus nerve stimulation (nVNS) (rather than
surgically implanted) paired with feeding to accelerate and enhance
the learning of feeding in neonates.
[0041] Referring now to FIG. 1A and FIG. 1B, an exemplary system
100 is depicted. In various embodiments, system 100 comprises
several components that can be used alone or in combination to
couple cranial nerve stimulation with feedback to train feeding
behavior in infants. For example, in some embodiments system 100
comprises bottle 102, wearable 122, and computer platform 134.
[0042] Bottle 102 can comprise any desired feeding bottle with
reservoir connected to a mouthpiece having a nipple or other
aperture suitable for engaging an infant's mouth typically used for
feeding infants, with the further addition of at least one flow
sensor 104, pressure sensor 106, gyroscope 108, accelerometer 110,
temperature sensor 112, volume sensor 114, and combinations
thereof. The at least one flow sensor 104 and pressure sensor 106
can be used to detect and measure the timing and amount of food
obtained by an infant during a feeding session. The at least one
gyroscope 108 and accelerometer 110 can be used to detect and
measure the position of bottle 102 and monitor feeding behavior
over time as a function of the movement of bottle 102. The at least
one temperature sensor 112 can be used to monitor the temperature
of bottle 102 to indicate whether the contents are at a suitable
temperature, or whether the contents are too cold or too hot for
consumption. The at least one volume sensor 114 can be used to
detect and measure the amount of food remaining in bottle 102. Any
suitable volume sensor 114 can be used, including float sensors,
ultrasonic level sensors, laser level sensors, and the like.
Additional sensors are also contemplated, such as suction sensors,
blood pressure sensors, pulse oximetry sensors, glucose sensors,
and the like. In some embodiments, bottle 102 can be powered by a
power source 116 (such as a battery or an electrical plug). In some
embodiments, bottle 102 can further include a wired or wireless
transmitter 118 for transmitting data collected by the various
sensors, and a non-transitory computer-readable medium 120
connected to a processor to store data collected by the various
sensors.
[0043] Wearable 122 comprises an assortment of sensing and
stimulating components, and can be in the form of an article of
clothing or harness that can be worn by a subject to position the
components adjacent to regions of sensing and stimulating interest.
Wearable 122 comprises at least one electrode 124. The at least one
electrode 124 includes stimulating electrodes and can also include
sensing electrodes. Stimulating electrodes are configured to
administer electrical stimulation, while sensing electrodes are
configured to measure a physiological response. For example,
sensing electrodes can include electrocardiography electrodes,
electromyography electrodes, electroencephalography electrodes, and
the like. In some embodiments, the stimulating electrodes are
electrically linked to the sensing electrodes. In various
embodiments, wearable 122 can further include one or more
additional sensors, such as temperature sensors, blood pressure
sensors, pulse oximetry sensors, glucose sensors, and the like.
Wearable 122 can further be powered by a power source 126 (such as
a battery or an electrical plug). In some embodiments wearable 122
can further include a wired or wireless transmitter 128 for
transmitting data collected by the various electrodes and sensors,
a wired or wireless receiver 130 for receiving instructions for
activating stimulating electrodes, and a non-transitory
computer-readable medium 132 connected to a processor to store data
collected by the various electrodes and sensors.
[0044] Computer platform 134 comprises a wired or wireless
transmitter 138 for transmitting instructions to wearable 122, a
wired or wireless receiver 140 to collected data from bottle 102,
wearable 122, or both, a non-transitory computer-readable medium
142 connected to a processor to store instructions and collected
data, and can be powered by a power source 136 (such as a battery
or an electrical plug).
[0045] As described above, the various components of system 100 can
be used alone or in combination to couple cranial nerve stimulation
with feedback. In a non-limiting first example, bottle 102 is
coupled with wearable 122. Bottle 102 can communicate with wearable
122 by way of transmitter 118 to receiver 130 that bottle 102 is in
position for feeding. As shown in FIG. 2, bottle 102 can sense a
minimum change in volume, flow, and/or pressure that passes a
threshold to initiate a trigger. Bottle 102 communicates to
wearable 122 to supplement feeding behavior by activating an
electrode 124 adjacent to a cranial nerve, thereby stimulating the
cranial nerve. Feeding behavior can be monitored and further
verified by bottle 102. Feeding behavior can also be monitored and
verified by an electrode 124 sensing cheek and jaw muscle
activation. Feeding can continue by timing and synchronizing
sensing of feeding initiation from bottle 102 and stimulation from
wearable 122.
[0046] In a non-limiting second example, wearable 122 can be used
alone as a closed loop system. A sensing electrode 124 adjacent to
one or more cheek and jaw muscles can be used to sense feeding
initiation through a minimum change in muscle activation that
passes a threshold to initiate a trigger. In response to the
trigger, wearable 122 supplements feeding behavior by activating a
stimulating electrode 124 adjacent to a cranial nerve. Feeding can
continue by timing and synchronizing sensing of feeding initiation
from a sensing electrode 124 and stimulation from a stimulating
electrode 124. In this manner, wearable 122 functions as a
closed-loop system between sensing a minimum cheek and jaw muscle
activation indicating feeding initiation and administering cranial
nerve stimulation.
[0047] Computer platform 134 can be used to supplement
communication between bottle 102 and wearable 122. Computer
platform 134 can also be used to facilitate operation, monitoring,
and data collection/storage for bottle 102, wearable 122, or both.
In some embodiments, computer platform 134 can be used to adjust
the timing and intensity of electrode stimulation in wearable 122
according to data received from bottle 102, wearable 122, or both.
In some embodiments, the timing and intensity of electrode
stimulation in wearable 122 is adjusted automatically to maintain
measurable parameters within thresholds set by computer platform
134. Measurable parameters include but are not limited to heart
rate, blood pressure, muscle activation rate, neural patterns,
bottle volume, bottle position, and the like. In some aspects of
the present invention, software executing the instructions provided
herein may be stored on a non-transitory computer-readable medium,
wherein the software performs some or all of the steps of the
present invention when executed on a processor.
[0048] Aspects of the invention relate to algorithms executed in
computer software. Though certain embodiments may be described as
written in particular programming languages, or executed on
particular operating systems or computing platforms, it is
understood that the system and method of the present invention is
not limited to any particular computing language, platform, or
combination thereof. Software executing the algorithms described
herein may be written in any programming language known in the art,
compiled or interpreted, including but not limited to C, C++, C#,
Objective-C, Java, JavaScript, Python, PHP, Perl, Ruby, or Visual
Basic. It is further understood that elements of the present
invention may be executed on any acceptable computing platform,
including but not limited to a server, a cloud instance, a
workstation, a thin client, a mobile device, an embedded
microcontroller, a television, or any other suitable computing
device known in the art.
[0049] Parts of this invention are described as software running on
a computing device. Though software described herein may be
disclosed as operating on one particular computing device (e.g. a
dedicated server or a workstation), it is understood in the art
that software is intrinsically portable and that most software
running on a dedicated server may also be run, for the purposes of
the present invention, on any of a wide range of devices including
desktop or mobile devices, laptops, tablets, smartphones, watches,
wearable electronics or other wireless digital/cellular phones,
televisions, cloud instances, embedded microcontrollers, thin
client devices, or any other suitable computing device known in the
art.
[0050] Similarly, parts of this invention are described as
communicating over a variety of wireless or wired computer
networks. For the purposes of this invention, the words "network",
"networked", and "networking" are understood to encompass wired
[0051] Ethernet, fiber optic connections, wireless connections
including any of the various 802.11 standards, cellular WAN
infrastructures such as 3G or 4G/LTE networks, Bluetooth.RTM.,
Bluetooth.RTM. Low Energy (BLE) or Zigbee.RTM. communication links,
or any other method by which one electronic device is capable of
communicating with another. In some embodiments, elements of the
networked portion of the invention may be implemented over a
Virtual Private Network (VPN).
[0052] It should be understood that the components of system 100
are not limited to use in training feeding behavior and can be used
to enhance infant development in a variety of manners. In some
embodiments, cranial nerve stimulation is effective in increasing
brain white matter integrity and inter-regional communication among
the various regions of the brain. In some embodiments, cranial
nerve stimulation is effective in enhancing motor function, such
that activities including head lifting, rolling, sitting up,
gripping, lifting, throwing, crawling, walking, climbing, and
descending can be trained and improved. In some embodiments,
cranial nerve stimulation is effective in modulating behavior.
Behavior modulation can include positive reinforcement for good
behavior, negative reinforcement for bad behavior, and the
reduction or treatment of neurological and psychological disorders
or injury.
[0053] It should be understood that the components of system 100
are not limited to use in infants and can be used in children,
adults, and the elderly. In various embodiments, the components of
system 100 are further applicable to animals, including mammals,
reptiles, birds, fish, and the like. In some embodiments, cranial
nerve stimulation is effective in treating muscle-related disorders
and rehabilitation, such as post-stroke upper and lower motor limb
rehab paradigms, wherein muscle groups involved in specific
rehabilitation paradigms are targeted. For example, referring now
to FIG. 3, components of system 100 (such as a sensing electrode
124 on wearable 122) can measure muscle activation in one or more
muscle groups of interest that passes a minimum threshold to
initiate a trigger. Wearable 122 can supplement muscle activation
by activating a stimulating electrode 124 adjacent to a cranial
nerve, thereby stimulating the cranial nerve. Further activation of
the one or more muscle groups of interest can be monitored and
verified by a sensing electrode 124. Muscle activation can continue
by timing and synchronizing sensing of muscle activation initiation
from a sensing electrode 124 and stimulation from a stimulating
electrode 124, such as in a closed loop system. In some
embodiments, cranial nerve stimulation is effective in modulating
muscular or neural diseases or disorders, including but not limited
to Parkinson's disease, dyskinesia, dystonia, and the like.
Cranial Nerve Stimulation Methods
[0054] The present invention is also based in part on methods for
administering noninvasive cranial nerve stimulation. As described
elsewhere herein, the methods are effective in enhancing
rehabilitation and recovery by improving neuroplasticity and
coupling muscle training with feedback.
[0055] In some embodiments, the methods relate to enhancing
oromotor skills. Referring now to FIG. 4, an exemplary method 200
is depicted. Method 200 begins with step 202, wherein a cranial
nerve stimulation system is provided, the system comprising at
least one sensing electrode and at least one stimulating electrode.
In step 204, the at least one sensing electrode is noninvasively
secured adjacent to a subject's cheek or jaw muscle, and the at
least one stimulating electrode is noninvasively secured adjacent
to a subject's cranial nerve. In step 206, the subject is provided
with a source of food. In step 208, muscle activation is measured
using the at least one sensing electrode that surpasses a minimum
threshold, indicating feeding initiation. In step 210, stimulation
is administered using the at least one stimulating electrode to the
cranial nerve in response to the measurement of muscle activation
surpassing the minimum threshold.
[0056] In some embodiments, the subject is an infant, and the
oromotor skills relate to suckling. In various embodiments, the
cranial nerve can be selected from the group consisting of the
trigeminal nerve, the facial nerve, the accessory nerve, the
hypoglossal nerve, the auricular branch of the vagus nerve, the
main bundle of the vagus nerve, and the like. In various
embodiments, the electrodes are noninvasively secured using an
adhesive, a clip, a patch, an ear plug, a head band, a neck brace,
a collar, a head covering, and the like. In some embodiments, the
steps are performed in the recited order. In various embodiments,
step 208 and step 210 are repeated in a closed loop system.
[0057] In some embodiments, the methods relate to muscle
rehabilitation. Referring now to FIG. 5, an exemplary method 300 is
depicted. Method 300 begins with step 302, wherein a cranial nerve
stimulation system is provided, the system comprising at least one
sensing electrode and at least one stimulating electrode. In step
304, the at least one sensing electrode is noninvasively secured
adjacent to a subject's muscle group of interest, and the at least
one stimulating electrode is noninvasively secured adjacent to a
subject's cranial nerve. In step 306, muscle group activation is
measured using the at least one sensing electrode that surpasses a
minimum threshold. In step 308, stimulation is administered using
the at least one stimulating electrode to the cranial nerve in
response to the measurement of muscle group activation surpassing
the minimum threshold.
[0058] In various embodiments, the cranial nerve can be selected
from the group consisting of the trigeminal nerve, the facial
nerve, the accessory nerve, the hypoglossal nerve, the auricular
branch of the vagus nerve, the main bundle of the vagus nerve, and
the like. In various embodiments, the electrodes are noninvasively
secured using an adhesive, a clip, a patch, an ear plug, a head
band, an arm band, a brace, a collar, a wrapping, and the like. In
some embodiments, the steps are performed in the recited order. In
various embodiments, step 306 and step 308 are repeated in a closed
loop system. In various embodiments, the methods of the present
invention select certain minimum thresholds of muscle activation.
In some embodiments, the methods select for a minimum threshold of
muscle activation that is determined by an absolute measurement.
For example, the minimum threshold of muscle activation can be
selected from an absolute value of about 0.1 .mu.V, 0.5 .mu.V,
1.mu.V, 5.mu.V, 10 .mu.V, 50 .mu.V, 100 .mu.V, 200 .mu.V, 300
.mu.V, 400 .mu.V, 500 .mu.V, 1 mV, 5 mV, 10 mV, 20 mV, 30 mV, 40
mV, or 50 mV.
[0059] In some embodiments, the methods select for a minimum
threshold of muscle activation that is determined by a change from
a base measurement taken at rest. For example, the minimum
threshold of muscle activation can be selected from an increase or
decrease of about 0.1 .mu.V, 0.5 .mu.V, 1.mu.V, 5.mu.V, 10 .mu.V,
50 .mu.V, 100 .mu.V, 200 .mu.V, 300 .mu.V, 400 .mu.V, 500 .mu.V, 1
mV, 5 mV, 10 mV, 20 mV, 30 mV, 40 mV, or 50 mV. In some
embodiments, the methods select for a minimum threshold of muscle
activation that is determined by a percentage of a typical maximum
potential of the muscle. For example, the minimum threshold of
muscle activation can be selected from about 1%, 2%, 3%, 4%, 5%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,
75%, 80%, 85%, 90%, or 95% of the typical maximum potential of the
muscle.
[0060] In various embodiments, the methods of the present invention
select certain parameters for cranial nerve stimulation. In some
embodiments, the methods select for an intensity of stimulation.
For example, the intensity of stimulation can be selected from
about 0.01 mA, 0.05 mA, 0.1 mA, 0.2 mA, 0.3 mA, 0.4 mA, 0.5 mA, 0.6
mA, 0.7 mA, 0.8 mA, 0.9 mA, 1 mA, 1.5 mA, 2 mA, 2.5 mA, 3 mA, 3.5
mA, 4 mA, 4.5 mA, 5 mA, 6 mA, 7 mA, 8 mA, 9 mA, or 10 mA. In some
embodiments the methods select for a frequency of stimulation. For
example, the frequency of stimulation can be selected from about 1
Hz, 2 Hz, 3 Hz, 4 Hz, 5 Hz, 6 Hz, 7 Hz, 8 Hz, 9 Hz, 10 Hz, 15 Hz,
20 Hz, 25 Hz, 30 Hz, 35 Hz, 40 Hz, 45 Hz, or 50 Hz. In some
embodiments, the methods select for a pulse width of stimulation.
For example, the pulse width of stimulation can be selected from
about 10 .mu.s, 20 .mu.s, 30 .mu.s, 40 .mu.s, 50 .mu.s, 60 .mu.s,
70 .mu.s, 80 .mu.s, 90 .mu.s, 100 .mu.s, 150 .mu.s, 200 .mu.s, 250
.mu.s, 300 .mu.s, 350 .mu.s, 400 .mu.s, 450 .mu.s, 500 .mu.s, 550
.mu.s, 600 .mu.s, 650 .mu.s, 700 .mu.s, 750 .mu.s, 800 .mu.s, 850
.mu.s, 900 .mu.s, 950 .mu.s, or 1 ms. In some embodiments, the
methods select for a duration of stimulation on and off periods.
For example, the duration of stimulation on and off periods can be
selected from about 0.1 seconds, 0.5 seconds, 1.5 seconds, 2
seconds, 2.5 seconds, 3 seconds, 3.5 seconds, 4 seconds, 4.5
seconds, 5 seconds, 10 seconds, 20 seconds, 30 seconds, 40 seconds,
50 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes,
10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 45
minutes, 50 minutes, and 1 hour. The on and off periods can have
the same duration or different durations.
EXPERIMENTAL EXAMPLES
[0061] The invention is further described in detail by reference to
the following experimental examples. These examples are provided
for purposes of illustration only, and are not intended to be
limiting unless otherwise specified. Thus, the invention should in
no way be construed as being limited to the following examples, but
rather, should be construed to encompass any and all variations
which become evident as a result of the teaching provided
herein.
[0062] Without further description, it is believed that one of
ordinary skill in the art can, using the preceding description and
the following illustrative examples, make and utilize the compounds
of the present invention and practice the claimed methods. The
following working examples therefore, specifically point out
exemplary embodiments of the present invention, and are not to be
construed as limiting in any way the remainder of the
disclosure.
Example 1
How to Measure a Baby's Suck? Closing the Loop on Transcutaneous
Auricular Vagus Nerve Stimulation (taVNS) to Enhance Oromotor
Development of Impaired Infants: Which Electrode is Best?
[0063] Feeding difficulty due to oromotor dyscoordination is a
primary concern for infants who are born preterm or suffer hypoxic
ischemic encephalopathy (HIE). Vagal Nerve Stimulation (VNS) can
increase neural plasticity, and when paired with rehabilitation,
can enhance motor learning. Recently, it was demonstrated that
non-invasive VNS can be accomplished via electrical stimulation of
the auricular branch of the vagus nerve using a new method called
transcutaneous auricular vagus nerve stimulation (taVNS). The goal
of the present study is to develop a closed-loop automatic system
that pairs taVNS with muscle activation from sucking, using
electromyography (EMG) as a trigger. This system may allow better
suck and stimulus pairing that is also less labor-intensive.
[0064] These investigations were designed to test the best location
for reference electrode placement and the fidelity of stimulation
paired with sucking. Three different EMG electrode placements (A,
B, C) were compared to optimize the specificity and sensitivity of
the automated system in 2 pre-term neonates enrolled in a larger
pilot trial (example shown in FIG. 6). Triggered stimulation was
delivered using a left ear electrode at 0.1 mA below perceptual
threshold, 25 Hz frequency, 500 .mu.s pulse width, for a 3.5 second
train. The primary outcomes of this study were specificity
(stimulations correctly paired to a visual suck, FIG. 7) and
sensitivity (visual sucks that triggered or occurred during
stimulation, FIG. 8).
[0065] Locations A, B, and C had a mean specificity of 49.3.+-.31.8
(n=3), 37.9.+-.13.4 (n=7), and 58.3.+-.18.5 (n=6), respectfully.
Locations A, B, and C had a mean sensitivity of 77.+-.15.9 (n=3),
82.+-.13.8 (n=7), and 75.2.+-.16.2 (n=6), respectively. Electrode
placement C was feasible and better tolerated. The placement
produced the highest average (60%) rate of stimulation induced by a
real visual suck while minimizing stimulation triggered by
non-visual suck (40%). All placements seemed to perform equally at
a rate of about 77-81% triggers induced by a visual suck. These
results demonstrate that EMG electrode position C was the most
efficient with 58% of stimulation trains correctly pairing with
visual sucks while maintaining good sensitivity to visual sucks.
Using EMG in a closed-loop taVNS system is a safe and effective way
to trigger taVNS stimuli in infants.
Example 2
Treating Neonates with Cranial Nerve Stimulation
[0066] In preterm infants with brain dysmaturation or term infants
with hypoxic ischemic encephalopathy (HIE), feeding difficulty is
the primary reason for delayed hospital discharge. Failure to
achieve full oral feedings may be due to closure of critical
developmental windows of neuroplasticity, or due to overt brain
injury in HIE infants. Current therapies are limited to feeding by
occupational or speech therapists once a day, and gastrostomy tube
(g-tube) placement.
[0067] The present study monitored intake of infants 20 days
post-oral (PO) feeding initiation. Infants that have failed feeding
on average for 49 days were determined to be g-tube candidates and
were enrolled in the cranial nerve stimulation trial (FIG. 9). 14
babies were analyzed in an interim analysis (FIG. 10). All babies
were g-tube candidates and had been attempting to feed orally for
an average of 49 days before enrollment. Treatment was administered
based on previous protocols (stimulation delivered using a left ear
electrode at 0.1 mA below perceptual threshold, 25 Hz frequency,
500 .mu.s pulse width, for a 3.5 second train). 57% of the babies
(8 of 14) reached the adequate PO intake (full feeds orally) that
is clinically required to be discharged without a g-tube. The
results demonstrate that in more than half of babies, cranial nerve
stimulation facilitates their rehabilitation, enhances
neuroplasticity, and facilitates motor learning.
[0068] FIG. 11 and FIG. 12 depict the statistical analysis of the
responder group and non-responder group. FIG. 11 shows that linear
regression comparison of responders before and during stimulation
treatment are significantly different, such that the slope
increases after treatment. FIG. 12 shows that linear regression
comparison of non-responders before and during stimulation
treatment are not significantly different.
[0069] Treatment candidates were imaged to monitor the effects of
treatment on brain development. Babies were scanned using MRI,
treated for 2-4 weeks, and scanned again to investigate changes in
white matter tracts. FIG. 13A and FIG. 13B demonstrate that cranial
nerve stimulation had a greater effect on brain white matter tract
integrity as indicated by fractional anisotropy (FA) and axial
kurtosis (K.sub..parallel.) in the responder group (full feed) than
in the non-responder group (g-tube). Specific white matter tracts
related to motor and sensorimotor integration were all
strengthened. Furthermore, FA changes in both responder and
non-responder groups were greater than expected with normal
development (FIG. 13A), demonstrating that there is more
inter-regional communication across the brain tract.
[0070] The disclosures of each and every patent, patent
application, and publication cited herein are hereby incorporated
herein by reference in their entirety. While this invention has
been disclosed with reference to specific embodiments, it is
apparent that other embodiments and variations of this invention
may be devised by others skilled in the art without departing from
the true spirit and scope of the invention. The appended claims are
intended to be construed to include all such embodiments and
equivalent variations.
* * * * *